Prostaglandin E2 (abbreviated as PGE2) has been known as a metabolite in the arachidonate cascade. It has been known that PGE2 possesses cyto-protective activity, uterine contractive activity, a pain-inducing effect, a promoting effect on digestive peristalsis, an awakening effect, a suppressive effect on gastric acid secretion, hypotensive activity and diuretic activity and so on.
A recent study has proved existence of various PGE subtype receptors possessing a different physical role from each other. At present, four receptor subtypes are known and they are called EP1, EP2, EP3, and EP4 (Negishi M., et al., J. Lipid Mediators Cell Signaling, 12, 379-391 (1995)).
It is thought that EP4 subtype receptor relates to inhibition of producing TNF-α and acceleration of producing IL-10. Therefore, the compounds which can bind on EP4 subtype receptor are expected to be useful for the prevention and/or treatment of immunological diseases (autoimmune diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjoegren's syndrome, chronic rheumarthrosis and systemic lupus erythematosus etc., and rejection after organ transplantation etc.), asthma, neuronal cell death, arthritis, lung failure, pulmonary fibrosis, pulmonary emphysema, bronchitis, chronic obstructive pulmonary disease, liver damage, acute hepatitis, nephritis (acute nephritis, chronic nephritis), renal insufficiency, hypertension, myocardiac ischemia, systemic inflammatory response syndrome, sepsis, hemophagous syndrome, macrophage activation syndrome, Still's disease, Kawasaki disease, burn, systemic granulomatosis, ulcerative colitis, Crohn's disease, hypercytokinemia at dialysis, multiple organ failure, and shock etc.
It is also thought that EP4 subtype receptor relates to protecting of mucosa. Therefore, the compounds which can bind on EP4 subtype receptor are expected to be useful for the prevention and/or treatment of ulcer of gastrointestinal tract such as gastric ulcer and duodenal ulcer etc. and stomatitis. It is also thought that EP4 subtype receptor relates to hair growth function. Therefore, the compounds which can bind on EP4 subtype receptor are expected to be useful for the prevention and/or treatment of hair-disadvantaged and alopecia. Furthermore, it is also thought that EP4 subtype receptor relates to maturation of cervix. Therefore, the compounds which can bind on EP4 subtype receptor are expected to be useful for the promoter of maturation of cervix.
Furthermore, the compounds which can bind on EP4 subtype receptor also have an action of accelerating bone formation, so it is expected to be useful for the prevention and/or treatment of diseases associated with decrease in bone mass, for example,    1) primary osteoporosis (e.g., primary osteoporosis followed by aging, postmenopausal primary osteoporosis, primary osteoporosis followed by ovariectomy etc.),    2) secondary osteoporosis (e.g., glucocorticoid-induced osteoporosis, hyperthyroidism-induced osteoporosis, immobilization-induced osteoporosis, heparin-induced osteoporosis, immunosuppressive-induced osteoporosis, osteoporosis due to renal failure, inflammatory osteoporosis, osteoporosis followed by Cushing's syndrome, rheumatoid osteoporosis etc.),    3) bone diseases such as bone metastasis of cancer, hypercalcemia, Paget's disease, bone loss (alveolar bone loss, mandibular bone loss, childhood idiopathic bone loss etc.), osteonecrosis etc.
Besides treatment of the above diseases, the present invention also includes a pharmaceutical composition for accelerating bone formation after bone operation (e.g., bone formation after fractures, bone formation after bone grafting, bone formation after operation of artificial joint, bone formation after spinal fusion and bone formation after the other operation for bone regeneration etc.), or promoting treatment thereof, or alternative treatment for bone grafting.
It is also thought that EP4 subtype receptor relates to induction of physiological sleeping and suppression of blood platelet aggregation, so such compounds are expected to be useful for the prevention and/or treatment of sleep disorder and thrombosis The compound which can bind an EP4 receptor selectively do not have inducing pain which may be caused by EP1, uterine relaxation which may be caused by EP2 and uterine contraction which may be caused by EP3, so they are thought to be agents having no effect on the above actions.
In the specification of U.S. Pat. No. 4,177,346, it is disclosed that the compound of formula (A)

(wherein QA is selected from the group consisting of —COOR3A, tetrazol-5-yl and —CONHR4A;
AA is single bond or cis-double bond;
BA is single bond or trans-double bond;
UA is

R2A is selected from the group consisting of α-thienyl, phenyl, phenoxy, mono-substituted phenyl and mono-substituted phenoxy, and the substituent is selected from the group consisting of chloro, fluoro, phenyl, methoxy, trifluoromethyl and C1-3 alkyl;
R3A is selected from the group consisting of hydrogen, C1-5 alkyl, phenyl and p-biphenyl;
R4A is selected from the group consisting of —COR5A and —SO2R5A;
R5A is selected from the group consisting of phenyl and C1-5 alkyl),
and a C5 epimer thereof, the salt of alkali metal and alkaline earth metals and ammounium salt of the compound which have carboxylate or tetrazol-5-yl.
And in the specification of JP-A-2001-181210, it is disclosed that the selective EP4 receptor agonist of formula (A) is useful for the treatment of osteoporosis.
And in the specification of United Kingdom Patent No. 1,553,595, the pyrrolidone derivatives of formula (B)

(wherein R1B is a straight- or branched-chain, saturated or unsaturated, aliphatic hydrocarbon radical having up to 10 carbon atoms, or a cycloaliphatic hydrocarbon radical having 3 to 7 carbon atoms, which radicals may be unsubstituted or substituted by one or more of the following:    e) a cycloalkyl group of 3 to 7 carbon atoms,    f) a phenyl, thienyl or furyl group which may carry one or two substituents selected from optionally halogenated alkyl group of 1 to 3 carbon atoms, halogen atoms and alkoxy group of 1 to 4 carbon atoms,
R2B is a straight- or branched-chain, saturated or unsaturated, aliphatic or cycloaliphatic hydrocarbon radical having up to 6 carbon atoms, or an araliphatic hydrocarbon radical having 7 or 8 carbon atoms, and
nB is the integer 2,3 or 4, the definitions of the symbols are excerpt), and a corresponding acid, a salt, especially the physiologically acceptable e.g. metal or amine, a salt thereof is disclosed.
In the specifications of United Kingdom Patent No.1,569,982, and United Kingdom Patent No.1,583,163, the compound close to the compound of formula (B) is disclosed.
In the specification of U.S. Pat. No. 4,320,136, the compound of formula (C)

(wherein AC is CH═CH (cis or trans), C≡C or CH2CH2;
RC is H, C1-C12 n-alkyl, branched alkyl or cycloalkyl etc.;
R1C is H, CH3 or C2H5;
R2C is phenyl or mono- or di-substituted phenyl, the substituent is selected from is selected from the group consisting of, F, Cl, CH3, OCH3, NO2 or CF3;
when R2C is phenyl or substituted phenyl,nC is 0-2, the definitions of the symbols are excerpt) is disclosed.
In the specification of WO00/03980, it is disclosed that the compound of formula (I-1) is useful as EP4 receptor binding agent.
In the specification of WO01/37877, it is disclosed that the EP4 receptor agonist of formula (I-1) is useful for treatment of diseases associated with decrease in bone mass.
It is disclosed that the EP4 receptor agonist of formulae (A) and (I-1) is useful for treatment of diseases associated with bone, there is a general description about topical administration. Therefore it is unproved that topical administration of the EP4 receptor agonist is useful for treatment of diseases associated with bone experimentally.
Four PGE2 subtype receptors possessing a different physical role from each other exist, and each subtype is called EP1, EP2, EP3, and EP4 and has a different pharmacological action. So the compounds which can bind on EP4 subtype receptor selectively and binds on the other subtype receptors weakly may be the drug with less side effect, because they show no any other activities. Therefore it is in need of finding the drug like this.
On the other hand, a lot of compounds which have the EP4 agonistic activity are found until now. However, all of them have a prostanoid skeleton, so it is thought that they influence circulatory system (e.g. blood pressure lowered or increasing of the heart rate), or cause side-effect such as diarrhea when they are administered by systemic administration such as oral administration or intravenous infusion. Therefore, they have significant problem that there is a limitation of the dose that can be administered safely.
As a disease associated with EP4 agonist, a lot of studies of diseases associated with decrease in bone mass have been done. It is also thought that systemic administration causes side-effects, so development of the drug with less side effects is expected. Finding a long-acting pharmaceutical which can be administrated topically is also expected.